PGD 2 /DP1 axis promotes liver regeneration by secreting Wnt2 in KCs in mice.

BACKGROUND AND AIMS: The liver possesses a remarkable regenerative capacity in response to injuries or viral infections. Various growth factors and cytokines are involved in regulating liver regeneration. Prostaglandin D 2 , a pro-resolution lipid mediator, is the most abundant hepatic prostanoid. However, the role of prostaglandin D 2 in the injury-induced liver regeneration remains unclear. APPROACH AND RESULTS: Two-thirds partial hepatectomy (70% PH), massive hepatectomy (85% resection), and carbon tetrachloride-induced chronic injury were performed in mice to study the mechanisms of live regeneration. Hepatic prostaglandin D 2 production was elevated in mice after PH. Global deletion of D prostanoid receptor (DP) 1, but not DP2, slowed PH-induced liver regeneration in mice, as evidenced by lower liver weight to body weight ratio, less Ki67 + hepatocyte proliferation, and G2/M phase hepatocytes. In addition, DP1 deficiency, specifically in resident KCs, and not in endothelial cells or HSCs, retarded liver regeneration in mice after PH. Conversely, the overexpression of exogenous DP1 in KCs accelerated liver regeneration in mice. Mechanistically, DP1 activation promoted Wnt2 transcription in a PKA/CREB-dependent manner in resident KCs and mediated hepatocyte proliferation through Frizzled8/ß-catenin signaling. Adeno-associated virus vector serotype 8-mediated Frizzled8 knockdown in hepatocytes attenuated accelerated liver regeneration in KC-DP1 transgenic mice after PH. Treatment with the DP1 receptor agonist BW245C promotes PH-induced liver regeneration in mice. CONCLUSIONS: DP1 activation mediates crosstalk between KCs and hepatocytes through Wnt2 and facilitates liver regeneration. Hence, DP1 may serve as a novel therapeutic target in acute and chronic liver diseases.

IL-2 promotes expansion and intratumoral accumulation of tumor infiltrating dendritic cells in pancreatic cancer.

This study aims to investigate the diagnostic potential of IL-2 for PDAC and develop a method to improve the dendritic cell (DC) based vaccine against PDAC. The gene expression data and clinical characteristics information for 178 patients with PDAC were obtained from The Cancer Genome Atlas (TCGA). DCs were isolated from Human peripheral blood mononuclear cells (PBMCs) and were cultured in 4 different conditions. DCs were pulsed by tumor cell lysates or KRAS G12D1 - 23 peptide, and then used to activate T cells. The mixture of DCs and T cells were administered to xenograft mouse model through the tail vein. The infiltration of DCs and T cells were detected by immunohistochemistry. The generation of KRAS G12D mutation specific cytotoxic T cells was determined by in vitro killing assay. We observed that PDAC patients with higher IL-2 mRNA levels exhibited improved overall survival and increased infiltration of CD8 + T cells, NK cells, naïve B cells, and resting myeloid DCs in the tumor microenvironment. IL-2 alone did not enhance DC proliferation, antigen uptake, or apoptosis inhibition unless co-cultured with PBMCs. DCs co-cultured with PBMCs in IL-2-containing medium demonstrated the strongest tumor repression effect in vitro and in vivo. Compared to DCs obtained through the traditional method (cultured in medium containing GM-CSF and IL-4), DCs cultured with PBMCs, and IL-2 exhibited increased tumor infiltration capacity, potentially facilitating sustained T cell immunity. DCs cultured in the PBMCs-IL-2 condition could promote the generation of cytotoxic T cells targeting tumor cells carrying KRAS G12D mutation.

CRISPR/Cas9-mediated gene knockout of Sj16 in Schistosoma japonicum eggs upregulates the host-to-egg immune response.

Schistosomiasis is an important, neglected tropical disease. Schistosoma japonicum can evade host attacks by regulating the host's immunity, causing continuous infection. However, interactions between the host's immune system and S. japonicum are unclear. Our previous research found that the Sj16 protein isolated from S. japonicum has an anti-inflammatory effect in the host. However, the role of Sj16 in the regulation of host immunity in S. japonicum infection is not clear. Here, we applied the CRISPR/Cas9 technique to knockout Sj16 in S. japonicum eggs and investigated the effect of Sj16 in regulating host immunity. We found egg viability decreased after Sj16 knockout. In addition, we found granulomatous inflammation increased, the T-cell immune response enhanced and the immune microenvironment changed in mice model injected with Sj16-knockout eggs by tail vein. These findings suggested that S. japonicum could regulate host immunity through Sj16 to evade the host immune attack and cause continuous infection. In addition, we confirmed the application of CRISPR/Cas9-mediated gene reprogramming for functional genomics in S. japonicum.

CEBPα/miR-101b-3p promotes meningoencephalitis in mice infected with Angiostrongylus cantonensis by promoting microglial pyroptosis.

BACKGROUND: Angiostrongylus cantonensis (A. cantonensis) infection can induce acute inflammation, which causes meningoencephalitis and tissue mechanical injury to the brain. Parasite infection-induced microRNAs play important roles in anti-parasite immunity in non-permissive hosts. miR-101b-3p is highly expressed after A. cantonensis infection; however, the role of miR-101b-3p and the transcription regulation of miR-101b-3p in A. cantonensis infection remain poorly characterized. RESULTS: In the present study, we found that miR-101b-3p inhibition alleviated inflammation infiltration and pyroptosis in A. cantonensis infection. In addition, we found that CCAAT/enhancer-binding protein alpha (CEBPα) directly bound to the - 6-k to - 3.5-k region upstream of miR-101b, and CEBPα activated miR-101b-3p expression in microglia. These data suggest the existence of a novel CEBPα/miR-101b-3p/pyroptosis pathway in A. cantonensis infection. Further investigation verified that CEBPα promotes pyroptosis by activating miR-101b-3p expression in microglia, and microglial pyroptosis further promoted inflammation. CONCLUSIONS: Our results suggest that a CEBPα/miR-101b-3p/pyroptosis pathway may contribute to A. cantonensis infection-induced inflammation and highlight the pro-inflammatory effect of miR-101b-3p. Video Abstract.

Schistosome egg-derived extracellular vesicles deliver Sja-miR-71a inhibits host macrophage and neutrophil extracellular traps via targeting Sema4D.

BACKGROUND: Macrophages and neutrophils are rapidly recruited around Schistosome eggs to form granulomas. Extracellular traps (ETs) of macrophages and neutrophils are part of the pathogen clearance armamentarium of leukocytes. Schistosome eggs possess the ability to resist attack by the host's immune cells and survive by employing various immune evasion mechanisms, including the release of extracellular vesicles (EVs). However, the specific mechanisms by which Schistosome egg-derived EVs (E-EVs) evade the immune response and resist attack from macrophage and neutrophil ETs remain poorly understood. In this study, we aimed to investigate the association between E-EVs and macrophage/neutrophil ETs. METHODS: EVs were isolated from the culture supernatant of S. japonicum eggs and treated macrophages and neutrophils with E-EVs and Sja-miR-71a. The formation of ETs was then observed. Additionally, we infected mice with S. japonicum, administered HBAAV2/9-Sja-miR-71a, and the formation of macrophage ETs (METs) and neutrophil ETs (NETs) in the livers was measured. Sema4D-knockout mice, RNA sequencing, and trans-well assay were used to clarify Sja-miR-71a in E-EVs inhibits METs and NETs formation via the Sema4D/ PPAR-γ/ IL-10 axis. RESULTS: Our findings revealed that E-EVs were internalized by macrophages and neutrophils, leading to the inhibition of METs and NETs formation. The highly expressed Sja-miR-71a in E-EVs targeted Sema4D, resulting in the up-regulation of IL-10 and subsequent inhibition of METs and NETs formation. Sema4D knockout up-regulated IL-10 expression and inhibited the formation of METs and NETs. Furthermore, we further demonstrated that Sja-miR-71a inhibits METs and NETs formation via the Sema4D/ PPAR-γ/ IL-10 axis. CONCLUSIONS: In summary, our findings provide new insights into the immune evasion abilities of Schistosome eggs by demonstrating their ability to inhibit the formation of METs and NETs through the secretion of EVs. This study enhances our understanding of the host-pathogen interaction and may have implications for the development of novel therapeutic approaches. Video Abstract.

Knockout of Sema4D alleviates liver fibrosis by suppressing AOX1 expression.

Liver fibrosis can occur in many chronic liver diseases, and no effective treatments are available due to the poorly characterized molecular pathogenesis. Semaphorin 4D (Sema4D) has immune functions and serves important roles in T cell priming. Here, we found that Sema4D was highly expressed in fibrotic liver, and the expression of Sema4D increased with hepatic stellate cells (HSCs) activation. Knockout of Sema4D alleviated liver fibrosis. Mechanistically, knockout of Sema4D alleviated liver fibrosis by suppressing the expression of AOX1 in retinol metabolism. Further investigation demonstrated that retinoic acid receptor α (RARA), an important nuclear receptor of retinoic acid, was reduced by Sema4D knockout during liver fibrogenesis. Sema4D knockout-mediated suppression of liver fibrosis was partly mediated by regulating the balance of Th1, Th2, Th17, and T-bet+Treg cells via inhibiting AOX1/RARA. Thus, targeting Sema4D may hold promise as a potential therapeutic approach for treating liver fibrosis.

Host liver-derived extracellular vesicles deliver miR-142a-3p induces neutrophil extracellular traps via targeting WASL to block the development of Schistosoma japonicum.

Schistosomiasis is an important neglected tropical disease. Interactions between the host immune system and schistosomes are complex. Neutrophils contribute to clearance of large pathogens primarily by releasing neutrophil extracellular traps (NETs). However, the functional role of NETs in clearing schistosomes remains unclear. Herein, we report that extracellular vesicles (EVs) derived from the liver of Schistosoma japonicum-infected mice (IL-EVs) induce NET release by delivering miR-142a-3p to target WASL and block the development of S. japonicum. WASL knockout accelerated the formation of NETs that blocked further development of S. japonicum. miR-142a-3p and NETs upregulated the expression of CCL2, which recruits macrophages that block S. japonicum development. However, S. japonicum inhibited NET formation in wild-type mice by upregulating host interleukin-10 (IL-10) expression. In contrast, in WASL knockout mice, IL-10 expression was downregulated, and S. japonicum-mediated inhibition of NET formation was significantly reduced. IL-EV-mediated induction of NET formation is thus an anti-schistosome response that can be counteracted by S. japonicum. These findings suggest that IL-EV-mediated induction of NET formation plays a key role in schistosome infection and that WASL is a potential therapeutic target in schistosomiasis and other infectious diseases.

Optical design of a reflective double-grating spectrometer to detect one branch in the pure rotational Raman spectrum of N2.

This paper presents the optical design of a high-resolution double-grating spectrometer for extracting the multiple lines in the Stokes or anti-Stokes branch of the pure rotational Raman spectra of nitrogen. The spectrometer is composed of collimating and focusing mirrors, two reflective gratings, and a linear detector. The structural parameters were calculated using geometric configuration, dispersion, and aberrational theory, and conditions for first-order correction of keystone distortion with divergent grating illumination were derived. Based on this method, we simulated a spectrometer with a 16-channel linear array photomultiplier tube, resulting in uniformly distributed single-branch lines on each detector channel. The resolution reached 0.225 nm per channel, and the keystone distortion was less than 0.7%. The spectrometer avoids the interference of elastic signals by not detecting them, enabling the extraction of atmospheric temperature profiles via separated single-branch lines with high precision. Our design provides a promising solution to extract atmospheric temperature profiles for pure rotational Raman lidar.

Salt stress-induced changes in soil metabolites promote cadmium transport into wheat tissues.

Soil salinity is known to improve cadmium (Cd) mobility, especially in arid soils. However, the mechanisms involved in how salt stress-associated metabolic profiles participate in mediating Cd transport in the soil-plant system remain poorly understood. This study was designed to investigate the effects of salinity-induced changes in soil metabolites on Cd bioavailability. Sodium salts in different combinations according to molar ratio (NaCl:Na2SO4=1:1; NaCl:Na2SO4:NaHCO3=1:2:1; NaCl:Na2SO4:NaHCO3:Na2CO3=1:9:9:1; NaCl:Na2SO4:NaHCO3:Na2CO3=1:1:1:1) were applied to the Cd-contaminated soils, which increased soil Cd availability by 22.36% and the Cd content in wheat grains by 36.61%, compared to the control. Salt stress resulted in soil metabolic reprogramming, which might explain the decreased growth of wheat plants and increased Cd transport from the soil into wheat tissues. For example, down-regulation of starch and sucrose metabolism reduced the production of sugars, which adversely affected growth; up-regulation of fatty acid metabolism allowed wheat plants to maintain a normal intracellular environment under saline conditions; up-regulation of the tricarboxylic acid (TCA) cycle was triggered, causing an increase in organic acid synthesis and the accumulation of organic acids, which facilitated the migration of soil Cd into wheat tissues. In summary, salt stress can facilitate Cd transport into wheat tissues by the direct effect of salt-based ions and the combined effect of altered soil physicochemical properties and soil metabolic profiles in Cd-contaminated soils.

Simulation and misalignment analysis of the gain ratio of a polarization Mie Raman lidar.

The gain ratio is a critical parameter in a polarization Mie lidar. Calibrating the gain ratio is essential in aerosol classification studies. We developed a ray-tracing-based simulation method to investigate the impact of mounting errors on the gain ratio. In this method, a computational model for each element of the lidar was built, and Zemax was used to simulate the lidar receiver to obtain the optical gain ratio by theoretical calculations. This method can analyze the influence of each element's mounting errors and offer a theoretical foundation for the machining and mounting accuracy of the lidar design. The correctness of the model was verified by applying it to a single-wavelength polarization Mie Raman lidar.

Simulation and misalignment analysis of the gain ratio of a polarization Mie Raman lidar: publisher's note.

This publisher's note serves to correct an error in Appl. Opt.61, 2881 (2022)APOPAI0003-693510.1364/AO.453852.

An increased posterior tibial slope is associated with a higher risk of graft failure following ACL reconstruction: a systematic review.

PURPOSE: The posterior tibial slope (PTS) is considered a risk factor for anterior cruciate ligament (ACL) injury. However, the influence of PTS on graft failure following ACL reconstruction remains relatively unknown. Therefore, this systematic review was conducted to investigate whether PTS could be a potential risk factor for graft failure after ACL reconstruction. METHODS: PubMed, EMBASE, Cochrane Library, Web of Science, China National Knowledge Infrastructure Database, and Wanfang Database were comprehensively searched from inception to March 31, 2021. Observational studies reporting the associations of medial tibial plateau slope (MTPS) or lateral tibial plateau slope (LTPS) with graft failure after ACL reconstruction were evaluated. RESULTS: Twenty studies involving 12 case-control studies, 4 retrospective studies and 4 cross-sectional studies including 5326 patients met the final inclusion criteria. The high heterogeneity and the characteristics of nonrandomized controlled trials limited data synthesis. Fifteen of the 20 included studies detected a significant association between increased PTS and ACL graft failure, while 5 studies concluded that increased PTS was not associated with ACL graft failure. Ten studies suggested that MTPS is associated with ACL graft failure, and six studies suggested that LTPS is associated with ACL graft failure. The mean MTPS values for nonfailure group ranged from 3.5° ± 2.5° to 14.4° ± 2.8°. For the graft failure group, MTPS ranged from 4.71° ± 2.41° to 17.2° ± 2.2°. The mean LTPS values for nonfailure group ranged from 2.9° ± 2.1° to 11.9° ± 3.0°. For the graft failure group, LTPS ranged from 5.5° ± 3.0° to 13.3° ± 3.0°. The reported PTS values that caused ACL graft failure was greater than 7.4° to 17°. CONCLUSION: Based on the current clinical evidence, increased PTS is associated with a higher risk of ACL graft failure after ACL reconstruction. Despite various methods of measuring PTS have high reliability, there is still vast disagreement in the actual value of PTS. LEVEL OF EVIDENCE: IV.

Linking Bacterial Growth Responses to Soil Salinity with Cd Availability.

This study investigated the effects of different types of saline stress on the availability of cadmium (Cd) and bacterial growth. Changes in soil physicochemical properties and DTPA-Cd content as well as microbial responses after the addition of salts were measured. The addition of 18 g kg-1 of salts with NaCl and Na2SO4 increased the available Cd content by up to 17.80%-29.79%. Respiration rate, biomass, and relative bacterial growth decreased with increasing salt concentrations. Estimated salinity tolerance of bacterial communities based on pollution-induced community tolerance. The salinity tolerance index EC50 of the bacterial community was estimated by logistic equation and ranged from 4.32-12.63 g kg-1. Structural equation modeling showed that soil salinity stress significantly affected Cd availability and bacterial community, while bacterial growth characteristics also contributed to reducing available Cd. We conclude that saline stress can alter soil Cd availability in soils by affecting the growth characteristics of soil bacterial communities.

MYC rearrangement but not extra MYC copies is an independent prognostic factor in patients with mantle cell lymphoma.

Mantle cell lymphoma (MCL) with MYC rearrangement (MYC-R) is rare and little is known about the importance of MYC extra copies (EC) in the absence of MYC-R in MCL patients. This study includes 88 MCL patients with MYC tested by fluorescence in situ hybridization and/or conventional cytogenetics, including 27 with MYC-R, 21 with MYC-EC, and 40 with normal (NL) MYC. MCL patients with MYC-R more often had blastoid/pleomorphic morphology; a higher frequency of CD10, MYC, and simultaneous MYC and BCL2 expression; a higher level of MYC; and a higher Ki67 proliferation rate (p<0.05) than those without MYC-R. Although patients with MYC-R more frequently received aggressive chemotherapy (p=0.001), their overall survival (OS) was significantly shorter than those without MYC-R. Compared with patients with MYC/BCL2 double hit lymphoma (DHL), patients with MYC-R MCL had a similar OS but more commonly had bone marrow involvement, stage 4 disease, and a different immunophenotype. MCL patients with MYC-EC showed an OS intermediate between those with MYC-R and MYC-NL, either all or only blastoid/pleomorphic MCL patients included. Multivariate analysis showed that MYC-R, but not MYC-EC, had an independent and negative impact on OS. In conclusion, MYC-R but not MYC-EC showed a higher MYC expression and is an adverse prognostic factor for MCL patients. Although the OS of MCL patients with MYC-R is similar to that of MYC/BCL2 DHL patients, these groups have different clinicopathologic features supporting the retention of MCL with MYC-R in the category of MCL, as recommended in the revised World Health Organization classification.

The mechanosensory and mechanotransductive processes mediated by ion channels and the impact on bone metabolism: A systematic review.

Mechanical environments were associated with alterations in bone metabolism. Ion channels present on bone cells are indispensable for bone metabolism and can be directly or indirectly activated by mechanical stimulation. This review aimed to discuss the literature reporting the mechanical regulatory effects of ion channels on bone cells and bone tissue. An electronic search was conducted in PubMed, Embase and Web of Science. Studies about mechanically induced alteration of bone cells and bone tissue by ion channels were included. Ion channels including TRP family channels, Ca2+ release-activated Ca2+ channels (CRACs), Piezo1/2 channels, purinergic receptors, NMDA receptors, voltage-sensitive calcium channels (VSCCs), TREK2 potassium channels, calcium- and voltage-dependent big conductance potassium (BKCa) channels, small conductance, calcium-activated potassium (SKCa) channels and epithelial sodium channels (ENaCs) present on bone cells and bone tissue participate in the mechanical regulation of bone development in addition to contributing to direct or indirect mechanotransduction such as altered membrane potential and ionic flux. Physiological (beneficial) mechanical stimulation could induce the anabolism of bone cells and bone tissue through ion channels, but abnormal (harmful) mechanical stimulation could also induce the catabolism of bone cells and bone tissue through ion channels. Functional expression of ion channels is vital for the mechanotransduction of bone cells. Mechanical activation (opening) of ion channels triggers ion influx and induces the activation of intracellular modulators that can influence bone metabolism. Therefore, mechanosensitive ion channels provide new insights into therapeutic targets for the treatment of bone-related diseases such as osteopenia and aseptic implant loosening.

Soil bacteria, genes, and metabolites stimulated during sulfur cycling and cadmium mobilization under sodium sulfate stress.

Sodium sulfate stress is known to improve cadmium (Cd) mobilization in soil and microbial sulfur oxidation, Cd resistance, and the accumulation of stress tolerance-associated metabolites has been correlated with increased soil Cd availability and toxicity. In this study, aerobic soil microcosms with Cd-contamination were stimulated with sodium sulfate to investigate its effects on soil microbial community structure, functional genes, and associated metabolite profiles. Metagenomic analysis revealed that sulfur oxidizing and Cd-resistant bacteria carried gene clusters encoding sox, dsr, and sqr genes, and znt, czc, and cad genes, respectively. Exposure to sodium sulfate resulted in the reprogram of soil metabolites. In particular, intensification of sulfur metabolism triggered an up-regulation in the tricarboxylic acid (TCA) cycle, which promoted the secretion of carboxylic acids and their precursors by soil bacteria. The accumulation of organic acids induced in response to high sodium sulfate dosages potentially drove an observed increase in Cd mobility. Pseudomonas and Erythrobacter spp. exhibited a high capacity for adaptation to heavy metal- or sulfur-induced stress, evident by an increased abundance of genes and metabolites for sulfur cycling and Cd resistance. These results provide valuable insights towards understanding the microbial mechanisms of sulfur transformation and Cd dissolution under saline stress.

Approximate Voigt function formula for laser-induced breakdown spectroscopy fitting.

Accurate and rapid spectrum fitting is very important for quantitatively analyzing laser-induced breakdown spectroscopy (LIBS). The Voigt function is often used to fit LIBS spectral lines. We propose a new approximate Voigt function formula. Based on the classic Lorentz-Gauss linear combination formula, a summation term was added that contained a specific convolution operation to improve the Voigt function's calculation and fitting accuracy. This formula can be used for the approximate calculation of the Voigt function with an overall accuracy of 0.31% and a full width at half-maximum internal accuracy of 0.25% when the ratio of Lorentzian linewidth to Gaussian linewidth is 1:1. The formula was then applied to LIBS data processing to fit four element spectral lines of calcium (Ca-393.37, 396.85, and 422.67 nm) and potassium (K-766.49 nm). The fitting results showed that this new approximate formula could fit at least seven data points, and compared with the complex plane partition method and the classic linear combination formula, the new formula had better fitting speed and accuracy.

Effect of soil leaching on the toxicity thresholds (ECx) of Zn in soils with different properties.

Currently, the scientific basis for establishing soil environmental criteria is lacking. In order to establish reasonable soil environmental criteria values suitable for soils with different properties, this study selected soils from 16 different sites to determine the toxicity threshold of Zn based on toxicity tests of barley root elongation. In addition, leaching treatments were set up in seven soils with different properties to eliminate the influence of the accompanying anions (Cl-) on the determination of the Zn toxicity threshold. The results indicated that the toxicity thresholds of different soils vary greatly. The EC10 and EC50 ranges of barley root elongation in 16 kinds of non-leached soils were 18.5 mgkg-1 to 1618.7 mgkg-1 and 277.9 mgkg-1 to 3179.8 mgkg-1, respectively. The hormesis effect appeared in the dose response of Zn, and relative barley root elongation reached more than 150%. Leaching significantly reduced the Zn toxicity in acidic soils. The variation ranges of the leaching factor (LF) in the seven soils were LF10 = 1.1-9.3, LF50 = 1.0-3.2. The LF prediction model indicated that pH explained 81.4% of the LF variation (p < 0.01). The soil pH, cation exchange capacity (CEC), and conductivity (EC) explained 97.8% of the EC50 variation in the leached soil (p < 0.01). The results provide reference values for Zn environmental criteria.

Therapeutic effects of higenamine combined with [6]-gingerol on chronic heart failure induced by doxorubicin via ameliorating mitochondrial function.

Higenamine (HG) is a natural benzylisoquinoline alkaloid isolated from Aconitum with positive inotropic and chronotropic effects. This study aimed to investigate the possible cardioprotective effects of HG combined with [6]-gingerol (HG/[6]-GR) against DOX-induced chronic heart failure (CHF) by comprehensive approaches. DOX-induced cardiotoxicity model in rats and H9c2 cells was established. Therapeutic effects of HG/[6]-GR on haemodynamics, serum indices and histopathology of cardiac tissue were analysed. Cell mitochondrial energy phenotype and cell mitochondrial fuel flex were measured by a Seahorse XFp analyser. Moreover, UHPLC-Q-TOF/MS was performed to explore the potential metabolites affecting the therapeutic effects and pathological process of CHF. To further investigate the potential mechanism of HG/[6]-GR, mRNA and protein expression levels of RAAS and LKB1/AMPK/Sirt1-related pathways were detected. The present data demonstrated that the therapeutic effects of HG/[6]-GR combination on CHF were presented in ameliorating heart function, down-regulation serum indices and alleviating histological damage of heart tissue. Besides, HG/[6]-GR has an effect on increasing cell viability of H9c2 cells, ameliorating DOX-induced mitochondrial dysfunction and elevating mitochondrial OCR and ECAR value. Metabolomics analyses showed that the therapeutic effect of HG/[6]-GR combination is mainly associated with the regulation of fatty acid metabolites and energy metabolism pathways. Furthermore, HG/[6]-GR has an effect on down-regulating RAAS pathway-related molecules and up-regulating LKB1/AMPKα/Sirt1-related pathway. The present work demonstrates that HG/[6]-GR prevented DOX-induced cardiotoxicity via the cardiotonic effect and promoting myocardial energy metabolism through the LKB1/AMPKα/Sirt1 signalling pathway, which promotes mitochondrial energy metabolism and protects against CHF.

Frequency, prognosis and treatment modalities of newly diagnosed small bowel cancer with liver metastases.

BACKGROUND: Population-based analysis for the liver metastases of small bowel cancer is currently lacking. This study aimed to analyze the frequency, prognosis and treatment modalities for newly diagnosed small bowel cancer patients with liver metastases. METHODS: Patients with small bowel cancer diagnosed from 2010 to 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Binary logistic regression analysis was performed to determine predictors for the presence of liver metastases at diagnosis. Kaplan-Meier method and Cox regression analyses were performed for survival analyses. RESULTS: A total of 1461 small bowel cancer patients with liver metastases at initial diagnosis were identified, representing 16.5% of the entire set and 63.9% of the subset with metastatic disease to any distant site. Primary tumor with poorer histological type, larger tumor size, later N staging, more extrahepatic metastatic sites, and tumor on lower part of small intestine had increased propensity of developing liver metastases. The combined diagnostic model exhibited acceptable diagnostic efficiency with AUC value equal to 0.749. Patients with liver metastases had significant poorer survival (P < 0.001) than those without liver metastases. In addition, combination of surgery and chemotherapy (HR = 0.27, P < 0.001) conferred the optimal survival for patients with adenocarcinoma, while the optimal treatment options for NEC and GIST seemed to be surgery alone (HR = 0.24, P < 0.001) and chemotherapy alone (HR = 0.08, P = 0.022), respectively. CONCLUSIONS: The combined predictor had a good ability to predict the presence of liver metastases. In addition, those patients with different histologic types should be treated with distinct therapeutic strategy for obtaining optimal survival.